Efficient solid-phase synthesis of clavulones via sequential coupling of α- and ω-chains

Article abstract of DOI:10.1021/ol036361b

We describe an efficient solid-phase synthesis of clavulones via the sequential coupling of the α- and ω-chains, involving two separate carbon - carbon bond-forming steps. The tetrahydropyranyl linker survived these reaction conditions and was cleaved without decomposing the unstable cross-conjugated dienones. Our methodology has allowed us to prepare six clavulone derivatives that are varied within the α-chain.

Full text of DOI:10.1021/ol036361b

ORGANIC
LETTERS
2
004
Vol. 6, No. 7
103-1106
Efficient Solid-Phase Synthesis of
Clavulones via Sequential Coupling of
r- and ω-Chains
1
†
†
‡,§
‡
Hiroshi Tanaka, Tsuyoshi Hasegawa, Makoto Iwashima, Kazuo Iguchi, and
,†
Takashi Takahashi*
Department of Applied Chemistry, Graduate School of Science and Engineering,
Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro, Tokyo 152-8552, Japan,
and School of Life Science, Tokyo UniVersity of Pharmacy and Life Science,
1432-1, Horinouchi, Hachioji-Shi
ttak@apc.titech.ac.jp
Received December 4, 2003
ABSTRACT
We describe an efficient solid-phase synthesis of clavulones via the sequential coupling of the r- and ω-chains, involving two separate
carbon−carbon bond-forming steps. The tetrahydropyranyl linker survived these reaction conditions and was cleaved without decomposing
the unstable cross-conjugated dienones. Our methodology has allowed us to prepare six clavulone derivatives that are varied within the
r-chain.
5
Chemical genetics is an effective methodology for the
elucidation of gene and protein function, in which biologi-
cally active small molecules are used as biomolecular
probes.1 Biologically active natural products and their
derivatives are often effective probes, as their structures have
already been fine-tuned to bind to their target proteins in
activities. The mechanism of their action is considered to
be based upon the reversible alkylation of certain proteins
at the C11 position (Figure 1). 12-Acetoxyl cyclopentenone
(
3) For a recent review of the synthesis of a natural product-like library,
see: (a) Nielsen, J. Curr. Opin. Chem. Biol. 2002, 6, 297-305.
4) For our reports of the combinatorial synthesis of small-molecule
libraries based on the structure of biologically active natural products, see:
a) Doi, T.; Hijikuro, I.; Takahashi, T. J. Am. Chem. Soc. 1999, 121, 6749-
750. (b) Hijikuro, I.; Doi, T.; Takahashi, T. J. Am. Chem. Soc. 2001, 123,
3716-3722. (c) Matsuda, A.; Doi, T.; Tanaka, H.; Takahashi, T. Synlett
001, 1101-1104. (d) Tanaka, H.; Zenkoh, T.; Setoi, H.; Takahashi, T.
Synlett 2002, 1427-1430. (e) Tanaka, H.; Ohno, H.; Kawamura, K.; Ohtake,
A.; Nagase, H.; Takahashi, T. Org. Lett. 2003, 5, 1159-1162. (f) Tanaka,
H.; Moriwaki, M.; Takahashi, M. Org. Lett. 2003, 5, 3807-3809. (g)
Tanaka, H.; Amaya, T.; Takahashi, T. Tetrahedron Lett. 2003, 44, 3053-
3057. (h) Takahashi, T.; Nagamiya, H.; Doi, T.; Peter, G.; Griffiths, P. G.;
Bray, A. M. J. Comb. Chem. 2003, 5, 414-428. (i) Takahashi, T.; Kusaka,
S.; Doi, T.; Sunazuka, T.; Omura, S. Angew. Chem., Int. Ed. 2003, 42,
5230-5234.
(
2
vivo during evolution. Therefore, the high-speed synthesis
(
6
of natural product-like libraries should lead to the rapid
3
,4
development of chemical probes that target proteins.
2
7
Cross-conjugated dienone prostanoids such as ∆ -pros-
1
taglandin A methyl ether (1) display varied biological
†
Tokyo Institute of Technology.
Tokyo University of Pharmacy and Life Science.
Current address: Department of Pharmacognosy, Faculty of Pharma-
‡
§
ceutical Sciences, Toyama Medical and Pharmaceutical University, 2630,
Sugitani, Toyama, Toyama 930-0194, Japan.
(5) Suzuki, M.; Mori, M.; Niwa, T.; Hirata, R.; Furuta, K.; Ishikawa,
T.; Noyori, R. J. Am. Chem. Soc. 1997, 119, 2376-2385.
(6) (a) Kikuchi, H.; Tsukitani, Y.; Iguchi, K.; Yamada, Y. Tetrahedron
Lett. 1982, 23, 5171-5174. (b) Kobayashi, M.; Yasuzawa, T.; Yoshihara,
M.; Akutsu, H.; Kyogoku, Y.; Kitagawa, I. Tetrahedron Lett. 1982, 23,
5331-5334.
(
1) (a) Schreiber, S. L. Bioorg. Med. Chem. 1988, 6, 1127-1152. (b)
Stockwell, B. R.; Hardwick, J. S.; Tong, J. K.; Schreiber, S. L. J. Am. Chem.
Soc. 1999, 121, 10662-10663.
(2) Tietze, L. F.; Bell, H. P.; Chandrasekhar, S. Angew. Chem., Int. Ed.
2
003, 42, 3996-4028.
1
0.1021/ol036361b CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/09/2004

Scheme 1
However, these methodologies provide 2,3-substituted 4-hy-
droxyl cyclopentanone derivatives. Therefore, the solid-phase
synthesis of clavulone derivatives with varying side-chains
should be attractive and challenging. Herein, we describe
an effective solid-phase synthesis of cross-conjugate pros-
tanoids that is based upon incorporation of the R- and
ω-chains via sequential carbon-carbon bond formation.
Our strategy for the solid-phase synthesis of clavulones 7
involves the (i) palladium-catalyzed coupling reaction of the
solid-supported cis-vinyl iodide 8 with alkylborane 10 to
afford stereoselectively the cis-configured ω-chain and (ii)
aldol reaction of cyclic and acyclic aldehydes 11 with the
cyclopentenone to form the cross-conjugated dienone system
Figure 1. Structure of Cross-Conjugated Dienone Prostanoids 1-3.
6
prostanoids such as clavulone I (2) and II (3) are particularly
interesting, as they show strong cytotoxicity. In clavulones,
the sequential Michael addition at the C11 and C7 positions
could potentially be irreversible, as the enol 5 generated by
double Michael addition via 4 could undergo a subsequent
â-elimination of the C12 acetoxyl group to provide enone
6. The irreversible reaction would be much more effective
at strongly inhibiting or modulating protein functioning
compared to the reversible reaction. Therefore, clavulone
derivatives bearing the appropriate side-chains could be
interesting biochemical probes. Unfortunately, however, all
syntheses of the 12-acetoxyl-cyclopentenone prostanoids are
(Scheme 1). The unstable dienone core is elaborated at the
final stages of the solid-phase synthesis. Significantly, the
two carbon-carbon bond-forming steps can be realized
without protecting group manipulations. The cyclopentenone
core 8 is immobilized at the C12 tert-hydroxyl group via a
tetrahydropyranyl linker, which is stable to the two sets of
reaction conditions. Cleavage from the solid-support under
mildly acidic conditions, followed by acetylation of the
resultant tert-alcohol, provides the clavulone derivatives 7.
Optically active cyclopentenone 9 can additionally be
prepared from (S)-4-hydroxycyclopentenone (12).
7
based upon traditional solution-phase methodology, and
none have been prepared by solid-phase technologies.
Solid-phase synthesis is an attractive method for the high-
8
speed synthesis of small molecule libraries, and recent
developments in solid-phase synthesis are now permitting
carbon-carbon bond formation on solid supports besides
9
amide bond formation. There have been several reports of
10
polymer-supported or solid-phase synthesis of prostanoids.
The preparation of cyclopentenone 9 bearing a cis-vinyl
iodide is shown in Scheme 2. Treatment of cyclopentenone
(
7) (a) Corey, E. J.; Mehrotra, M. J. Am. Chem. Soc. 1984, 106, 3384.
(
b) Nagaoka, H.; Miyakoshi, T.; Yamada, Y. Tetrahedron Lett. 1984, 25,
3
1
2
1
3
2
621-3624. (c) Hashimoto, S.; Arai, Y.; Hamanaka, N. Tetrahedron Lett.
985, 26, 2679-2682. (d) Shibasaki, M.; Ogawa, Y. Tetrahedron Lett. 1985,
6, 3841-3844. (e) Ciufolini, M. A.; Zu, S. J. Org. Chem. 1998, 63, 1668-
675. (f) Klunder, A. J. H.; Zwanenburg, B. Tetrahedron Lett. 1991, 32,
131-3132. (g) Takeda, K.; Nakajima, A.; Yoshii, E. Synlett 1997, 255-
56. (h) Zhu, J.; Yang, J.-Y.; Klunder, A. J. H.; Liu, Z.-Y.; Zwanenburg,
1
2 with 3-trimethylsilyl-2-propynyllithium in THF at -78
°C gave stereoselectively diol 13 in 75% yield without
11
racemization. Protection of the two hydroxyl groups in 13
with triethysilyl chloride and triethylamine provided disilyl
B. Tetrahedron 1995, 51, 5847-5870. (i) Tius, M. A.; Hu, H.; Kawakami,
J. K.; Busch-Petersen, J. J. Org. Chem. 1998, 63, 5971-5976. (j)
Akhmetavaleev, R. R.; Baibulatov, G. M.; Nuriev, I. F.; Miftakhov, M. S.
Russ. J. Org. Chem. 2001, 37, 1079-1082. (k) Akhmetavaleev, R. R.;
Baibulatov, G. M.; Nuriev, I. F.; Shitikova, O. V.; Miftakhov, M. S. Russ.
J. Org. Chem. 2001, 37, 1083-1087. (l) Roulland, E.; Monneret, C.; Florent,
J.-C. J. Org. Chem. 2002, 67, 4399-4406. (m) Kuhn, C.; Skaltsuounis, L.;
Monneret, C.; Florent, J.-C. Eur. J. Org. Chem. 2003, 2585-2595 and
references therein
ether 14; this was followed by iodination of the terminal
acetylene with AgNO /NIS to afford iodoalkyne 15 in 90%
3
(9) (a) Lorsbach, B. A.; Kurth, M. J. Chem. ReV. 1999, 99, 1549-1582.
(b) Sammelson, R. E.; Kurth, M. J. Chem. ReV. 2001, 101, 137-202.
(10) (a) Chen, S.; Janda, K. D. J. Am. Chem. Soc. 1997, 119, 8724-
8725. (b) Thompson, L. A.; Moore, F. L.; Moon, Y.-C.; Ellman, J. A. J.
Org. Chem. 1998, 63, 2066-2067. (c) Lee, K. J.; Angulo, A.; Ghazal, P.;
Janda, K. D. Org. Lett. 1999, 1, 1859-1862. (d) Manzotti, R.; Thag, S.-
Y.; Janda, K. D. Tetrahedron 2000, 56, 7885-7892. (e) Dragoli, D. R.;
Thompson, L. A.; O’Brien, J.; Ellman, J. A. J. Comb. Chem. 1999, 1, 534-
539.
(8) (a) Sencei, P. Solid-Phase Synthesis and Combinatorial Technology;
Wiley-Interscience: New York, 2000. (b) Dorwald, F. Z. Organic Synthesis
on Solid Phase; Wiley-VCH: New York; 2000. (c) Roland, E. D. J. Comb.
Chem. 2002, 369-418. (d) Handbook of Combinatorial Chemistry; Nico-
laou, K. C., Hanko, R., Hartwig, W., Eds.; Wiley-VCH: Weinheim; 2002;
Vols. 1 and 2.
(11) Optical purity of 13 was estimated by 1H NMR analysis of the
corresponding MTPA ester of the secondary alcohol to be >98%ee.
1104
Org. Lett., Vol. 6, No. 7, 2004

Scheme 2a
Scheme 3a
a
Reagents and conditions: (a) 1-trimethylsilyl-1-propyne, lithium
diisopropyl amide, THF, -78 °C, 85%; (b) triethylsilyl chloride,
imidazole, CH Cl , rt; (c) AgNO , N-iodosuccinimide, rt, 83% for
two steps; (d) Cy BH, Et O, rt, then AcOH, 82%; (e) CSA, MeOH,
°C; (f) MnO , CH Cl /benzene (1/2), rt, 75% for two steps.
2
2
3
2
2
0
2
2
2
yield (two steps). Structure determination of 15 was achieved
1
by analysis of H NOE spectra. Stereoselective reduction of
the iodoalkyne was accomplished by hydroboration followed
by acid hydrolysis of the vinyl borane to yield the cis-vinyl
iodide 16 in 73% yield.12 Removal of the two triethysilyl
ethers was achieved under mildly acidic conditions and
followed by a selective oxidation of the resultant secondary
hydroxyl with manganese dioxide to provide ketone 9 in 93%
yield (two steps).
a
Reagents and conditions: (a) 3,4-dihydro-2H-pyran-2-yl-
methoxymethyl polystyrene, PPTS, CH
pentanyl 9-BBN, Pd(PPh ) , 2 M Na CO (aq), THF, 45 °C, 12 h;
2 2
Cl , 40 °C, 20 h; (b)
Immobilization of ketone 9 on solid-support (Scheme 3)
3
4
2
3
(
2 2
c) TFA/CH Cl , rt, 30 min; (d) KHMDS, THF, -78 °C, then 8a-
2 2
was achieved by exposing a 0.5 M CH Cl solution of alcohol
2 2 2
h, -78 °C, 2 h; (e) TFA/CH Cl , rt, 30 min; (f) Ac O, Py., DMAP,
9
to 3,4-dihydro-2H-pyran (DHP) polystyrene (0.72 mmol/
rt, 2 h.
13
g) with pyridinium p-toluenesulfonate (PPTS) at 40 °C;
the product of the reaction was the solid-supported ketone
8
. Treatment of 8 under mild aqueous acidic conditions
the corresponding cross-conjugate dienone 21a in 52% yield
along with ketone 19 in 15% yield. Lithium diisopropylamide
(LDA), which has been used in the reported solution-phase
syntheses of clavulones, did not work well for the solid-
phase synthesis. Subjection of the (Z)-aldehyde 11b to these
reaction conditions resulted in partial isomerization of the
double bond to provide 21b in 45% yield along with the
(E)-isomer 21a in 7% yield. Further examination using the
isolated (Z)-isomer 21b revealed that isomerization of the
double bond occurred under the mildly acidic cleavage
conditions.
To demonstrate the applicability of this solid-phase
synthesis, we conducted the solid-phase synthesis of clavu-
lone and clavulolactone-related compounds (Scheme 3 and
Table 1). Aldol reaction using aldehydes 11c and 11d
provided the corresponding coupled products 21c and 21d
in moderate yield. However, coupling with the two cyclic
aldehydes 11e and 11f did not provide the corresponding
clavulolactones 21e and 21f under the same reaction condi-
tions due to the instability of the cyclic aldehydes 11e and
resulted in the recovery of 9 in 75% yield based upon the
resin loading. With 8 in hand, and its structural integrity
confirmed, the two side-chains were sequentially introduced.
Treatment of the solid-supported vinyl iodide 8 with Pd-
(
PPh
nonane (9-BBN), prepared by in situ hydroboration of
-pentene, provided solid-supported 4-substituted cyclopen-
3 4 2 3
) , 2 M aq Na CO , and pentyl 9-9-borabicyclo[3.3.1]-
1
14
tenone 17 in 78% yield; its structure was confirmed by
purification of the released ketone 18. Aldol condensation
of the solid-supported ketone 17 to couple the R-chain was
examined using aldehydes 11a and 11b. Exposure of the
solid-supported ketone 17 to a THF solution of potassium
hexamethyldisilazide (KHMDS) at -78 °C for 40 min,
followed by addition of aldehyde 11a, provided the solid-
supported trienones 20a. Cleavage from the resin under
mildly acidic conditions, followed by acetylation, provided
(
12) Corey, E. J.; Cashman, J. R.; Eckrich, T. M.; Corey, D. A. J. Am.
Chem. Soc. 1985, 107, 713-715.
13) Thompson, L. A.; Ellman, J. A. Tetrahedron Lett. 1994, 35, 9333-
336.
14) (a) Suzuki, A.; Miyaura, N.; Ishikawa, T.; Sasaki, H.; Ishikawa,
(
9
1
1f under the basic conditions. To overcome this problem,
(
we designed the acyclic silyoxy aldehydes 11g and 11h.
Deprotection of the silyl ether followed by cyclization under
M.; Satoh, M. J. Am. Chem. Soc. 1989, 111, 314-321. (b) Miyaura, N.;
Suzuki, A. Chem. ReV. 1995, 95, 2457-2483.
Org. Lett., Vol. 6, No. 7, 2004
1105

13
NMR, C NMR, HR-MS) of the synthetic clavulone II were
6
a
identical to those of the isolated material.
Table 1. Solid-Phase Synthesis of Clavulone Derivatives 21
In summary, we have demonstrated an efficient solid-phase
synthesis of clavulone derivatives by a reaction sequence
involving palladium-catalyzed coupling and aldol condensa-
tion. Using this flexible methodology, the synthesis of six
clavulones was accomplished. The biological activity of the
clavulone derivatives is currently being explored. The
synthesis of a combinatorial library of clavulones is in
progress.
entry
aldehyde
product
E/Z ratio
yielda (%)
1
2
3
4
5
6
11c
11d
11e
11f
11g
11h
21c
21d
21e
21f
21e
21f
E only
1:11b
52%
55%
0%
0%
44%
49%
E only
1:10b
a
Isolated yield is based on the solid-support ketone 17. b Ratio was
calculated on the basis of the isolated yields.
Acknowledgment. This work was supported by a Grand-
in-Aid for Scientific Research on a Priority Area (S) from
the Ministry of Education, Culture, Sports, Science, and
Technology. (Grant-in-Aid No. 14103013).
the acidic release conditions provided the γ-butanolide
derivatives. The aldol condensation of each of the aldehydes
1
1g and 11h with ketone 17, followed by acetylation after
Supporting Information Available: Experimental pro-
cedures for synthesis and full characterization for compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
cleavage under acidic conditions, provided the lactones 21e
and 21f in 44 and 49% yields, respectively. A small amount
of (E)-olefin 21e was observed when (Z)-olefin 11h was
used. Further purification of diastereomer 21c was performed
1
by HPLC to give clavulone II (3). The analytical data ( H
OL036361B
1106
Org. Lett., Vol. 6, No. 7, 2004